Abstract The aim of this paper is the evaluation of the thermal behavior of a massive building under the synergic combination of natural ventilation and thermal inertia. In particular, an experimental study has been carried out on Villa San Saverio, which is a massive historical building located in Catania (Italy), in order to characterize its thermal performance under dynamic conditions, and to evaluate the potential decrease of the indoor overheating by exploiting natural ventilation and limiting both internal and solar gains. The analysis of the transient behavior of this building permits to highlight the possibility of diversifying the time lag in relation to the wall orientation. A time lag of 12.00–14.00h can be suggested for the walls due East. On the other hand, a time lag of around 8.00h can be suggested to achieve the same result for the walls due West. Time lags higher than the values suggested above could be not fully functional, since delaying further the heat transfer from the wall to its inner surface, reduces the useful time for exploiting the cooling effect of the nocturnal ventilation. The results of both measurements and simulations indicate that high thermal inertia mass combined with natural ventilation prevents phenomena of overheating and ensures good comfort levels in occupied buildings, reducing the needs of cooling systems during summer period.